Title: Antiviral%20chemotherapy
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2The head of a pin can hold five hundred million
rhinoviruses (cause of the common cold).One
sneeze can generate an aerosol of enough cold
viruses to infect thousands of people!
3Antiviral chemotherapy
- Virus Structure and Replication
- Viruses are the smallest infective agent,
effectively consisting of nucleic acid (DNA
or RNA) enclosed in a protein coat. - Viruses are intracellular parasites with
no, or little, metabolic machinery of their
own. - They have to borrow the biochemistry of
the host cell to succeed and grow (this is
what makes selective antiviral therapy so
difficult).
4Antiviral chemotherapy
- The virus attaches to specific receptors on
the host cell surface which are normal
membrane components. Usually ion channels,
neurotransmitter receptors. - The receptor/virus complex enters the cell
by receptor-mediated endocytosis during which
the virus coat may be removed. - The nucleic acid of the virus then hijacks
the cellular machinery for replicating
viral nucleic acids and proteins for the
manufacture of new virus particles.
5Antiviral chemotherapy
- The genome of DNA viruses enters the cell
nucleus and uses host RNA polymerase to
produce virus-specific proteins. - After assembly of coat proteins around the
viral DNA, complete virions are released by
budding or after cell lyses. - Generally, RNA virus replication occurs
solely in the cytoplasm and doesnt involve
the cellular nucleus. (influenza are an
exception since they have a requirement for
active cellular transcription).
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7Treatment of Herpesviruses Varicella-zoster,Cyto
megalavirus,Herpes simplex
8Anti-metabolites
- False DNA building blocks or nucleosides. A
nucleoside consists of a nucleobase and the sugar
deoxyribose. - In antimetabolites, one of the components is
defective. In the body, the abnormal nucleosides
undergo bioactivation by attachment of three
phosphate residues - Acyclovir has both specificity of the highest
degree and optimal tolerability, because it
undergoes bioactivation only in infected cells,
where it preferentially inhibits viral DNA
synthesis.
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10Acyclovir
- A virally coded thymidine kinase (specific to
H.simplex and varicella-zoster virus) performs
the initial phosphorylation step the remaining
two phosphate residues are attached by cellular
kinases. - Acyclovir triphosphate inhibits viral DNA
polymerase resulting in chain termination. - It is 30-fold more potent against the virus
enzyme than the host enzyme. -
- Acyclovir is active against herpes simplex
and varicellar-zoster virus. - It is rapidly broken down in cells, is
orally active and is relatively non-toxic
systemically.
11Acyclovir and Valacyclovir (pro-drug, better
availability)
- A Guanine analogue with antiviral for Herpes
group only
Acyclovir
AcycloGMP
AcycloGTP
Thymidine kinase
Cellular kinases
Viral 200x affinity of mammalian
- Inhibits viral DNA polymerase selectively
- Incorporated into DNA and terminates synthesis
Resistance 1. ? activity of thymidine kinase 2.
altered DNA polymerase
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13Acyclovir
- Acyclovir is used to treat
- Herpes simplex infections (genital herpes,
and herpes encephalitis). - Chickenpox in immuno-compromised patients.
- Prophylactically in patients treated with
immunosuppressant drugs or radiotherapy who
are in danger of infection by reactivation
of latent virus. - Prophylactically in patients with frequent
recurrences of genital herpes.
14- Oral acyclovir has multiple uses. In first
episodes of genital herpes, oral acyclovir
shortens the duration of symptoms by
approximately 2 days, the time to lesion healing
by 4 days, and the duration of viral shedding by
7 days. In recurrent genital herpes, the time
course is shortened by 12 days. - Oral acyclovir is only modestly beneficial in
recurrent herpes labialis. - Topical acyclovir cream is substantially less
effective than oral therapy for primary HSV
infection. It is of no benefit in treating
recurrent genital herpes.
15Acyclovir
- Common adverse drug reactions are nausea,
vomiting, diarrhea and headache. - Additional common adverse effects, when acyclovir
is administered IV, include - Renal insufficiency and neurologic toxicity
-
- However, incommon with adequate hydration and
- avoidance of rapid infusion rate.
16Docosanol
- Docosanol is a saturated 22-carbon aliphatic
alcohol that inhibits fusion between the plasma
membrane and the HSV envelope, thereby preventing
viral entry into cells and subsequent viral
replication. - Topical docosanol 10 cream is available without
a prescription application site reactions occur
in approximately 2 of patients. - When applied within 12 hours of the onset of
prodromal symptoms, five times daily, median
healing time was shortened by 18 hours compared
with placebo in recurrent orolabial herpes.
17Ganciclovir
- Mechanism like Acyclovir
- Active against all Herpes viruses including CMV
(100 time than acyclovir) - Low oral bioavailability given I.V.
- Most common adverse effect bone marrow
suppression (leukopenia 40, thrombocytopenia
20) and CNS effects (headache, behavioral,
psychosis, coma, convulsions). - 1/3 of patients have to stop because of adverse
effects - Drug of choice for CMV infections retinitis,
pneumonia, colitis.
18Foscarnet
- An inorganic pyrophosphate analog
- Active against Herpes (I, II, Varicella , CMV),
including those resistant to Acyclovir and
Ganciclovir. - Direct inhibition of DNA polymerase and Reverse
Transcriptase - Nephrotoxicity (25) most common side effect
- Use (1) CMV retinitis and other CMV infections
instead of ganciclovir - (2) H. simplex resistant to Acyclovir.
- (3) HIV.
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20Vidarabine
- Inhibits virally induced DNA polymerase more
strongly than it does the endogenous enzyme. - Vidarabine is a chain terminator and is
active against herpes simplex, varicella
zoster, and vaccinia are especially
sensitive. - Its use is now limited to topical treatment of
severe herpes simplex infection. Before the
introduction of the better tolerated acyclovir,
vidarabine played a major part in the treatment
of herpes simplex encephalitis. - Its clinically used in treatment of
immunocompromised patients with herpetic and
vaccinia keratitis and in keratoconjunctivitis.
21- Treatment of respiratory virus infection
- Influenza A B
- Respiratory suncytial virus (RSV)
22Attachment Inhibitors
- The primary antiviral mechanism of Amantadine and
Rimantadine is to block the viral membrane
matrix protein, which function as an ion channel
that is required for the fusion of the viral
membrane with the cell membrane. - Their clinical use is limited to Influenza A
infection. - They are very effective in preventing infection
if the treatment is begun at the time of-or prior
to- exposure to the virus.
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24Attachment Inhibitors
- Side effects of Amantadine are mainly associated
with the CNS, such as ataxia and dizziness. - While Rimantadine produce little CNS effect
because it does not penetrate the blood brain
barrier. - Both should be used with caution in pregnant and
nursing women.
25Neuroaminidase inhibitors
- Oseltamivir and Zanamavir
- Mechanism of action
- Viral neuraminidase catalyzes cleavage of
terminal sialic acid residues attached to
glycoproteins and glycolipids, a process
necessary for release of virus from host cell
surfaces. - Neuraminidase inhibitors thus prevent release of
virions from infected cell
26Neuroaminidase inhibitors
- Administration of neuraminidase inhibitors is a
treatment that limits the severity and spread of
viral infections. - Neuraminidase inhibitors are useful for combating
influenza infection - zanamivir, administered by inhalation
- oseltamivir, administered orally.
- Toxicities
- Exacerbation of reactive airway disease by
zanamavir - Nausea and vomiting for oseltamivir
27oseltamivir
- Early administration is crucial because
replication of influenza virus peaks at 2472
hours after the onset of illness. - When a 5-day course of therapy is initiated
within 3648 hours after the onset of symptoms,
the duration of illness is decreased by 12 days
compared with those on placebo, - severity is diminished, and the incidence of
secondary complications in children and adults
decreases. - Once-daily prophylaxis is 7090 effective in
preventing disease after exposure.
28Ribavirin
- It is an antimetabolite that inhibits influenza
RNA polymerase non-competitively in vitro but
poorly in vivo. - An aerosol form is used against RSV (respiratory
syncytial virus) and the drug is used
intravenously against Lassa fever. - Adverse reactions includes Anemia due to
hemolysis and bone marrow suppression
29Antiretroviral agents
30HIV Life Cycle
Step 1 Fusion
Step 3 Integration
reverse transcriptase
HIV
Step 5 Packaging and Budding
Step 2 Transcription
Step 4 Cleavage
31Azidothymidine (Zidovudin(AZT))
- It is a potent antagonist of reverse
transcriptase, It is a chain terminator. - Cellular enzyme phosphorylate AZT to the
triphosphate form which inhibits RT and causes
chain termination - It is widely use in the treatment of AIDS
(The only clinical use). - AZT is toxic to bone marrow, for example, it
cause severe anaemia and leukopenia In patient
receiving high dose. Headache is also common
32Didanosine (Dideoxyinosine)
- Didanosine act as chain terminators and
inhibitors of reverse transcriptase because
they lack a hydroxyl group. - is phosphorylated to the active metabolite of
dideoxyadenosine triphosphate - It is used in the treatment of AIDS (second
drug approved to treat HIV-1 infection). - They are given orally,
- and their main toxicities are pancreatitis,
peripheral neuropathy, GI disturbance, bone
marrow depression.
33Non-nucleoside Non-competitive RT inhibitors
(1) bind to viral RT, inducing conformational
changes that result in enzyme inhibition (2)
Combination therapy with AZT (resistant mutants
rapidly emerge, little use in monotherapy) (3)
Resistance mutations will be at different
sites
34Non-nucleoside Non-competitive RT inhibitors
- Nevirapine Approved for AIDS patients, Good
blocker of mother to child transmission
(perinatal - breast feeding) - Single dose at delivery reduced HIV transmission
by 50 - Single dose to baby by 72 hours
NNRTIs Adverse Effects RASH!! CNS effects
(e.g. sedation, insomnia, vivid dreams,
dizziness, confusion, feeling of disengagement)
35Rash
Rash, occurs in up to 20 of patients, usually in
the first 46 weeks of therapy. Although
typically mild and self-limited, rash is
dose-limiting in about 7 of patients. Women
appear to have an increased incidence of rash.
When initiating therapy, gradual dose
escalation over 14 days is recommended to
decrease the incidence of rash.
36Protease Inhibitors
- HIV Protease Inhibitors have significantly
alter the course of the HIV disease. - All are reversible inhibitors of HIV Protease-the
viral enzyme responsible for cleavage of viral
polyprotein into number of essential enzymes
(reverse transcription, polymerase). - Examples are Saquinavir, and Ritonavir.
- They are orally active, side effects include
GI disturbances and hyperglycemia, interact
with cytochrome P450. buffalo hump
37Anti-Viral Chemotherapy
GAG/POL polyprotein
GAG
Integrase
Polymerase
Protease
Retrovirus --- HIV
38Anti-Viral Chemotherapy
GAG
Integrase
Polymerase
Protease folds and cuts itself free
39Anti-Viral Chemotherapy
GAG
Integrase
Polymerase
Protease cuts at a site between the integrase and
polymerase
40Anti-Viral Chemotherapy
GAG
Integrase
polymerase
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42New targets
- Enfuvirtide is Peptides derived from gp41 can
inhibit infection, probably by blocking the
interaction of gp41 with cell membrane proteins
during fusion. - Raltegravir (Integrase Inhibitor) targets
integrase, an HIV enzyme that integrates the
viral genetic material into human chromosomes, a
critical step in the pathogenesis of HIV. - Maraviroc It blocks the interaction between
chemokine receptor CCR5 and HIV gp120.
43(HAART)
- Highly active anti-retroviral therapies
- Combination therapies (triple drug cocktail,
HAART) are very effective and can reduce viral
load in the patient below detectable levels
implying that HIV replication has ceased. - examples (1) NNRTIBased Regimens (1-NNRTI
2NRTIs) - (2) PI-Based Regimens (1 or 2 PIs 2
NRTIs) - The trouble with all of these complicated drug
regimens is compliance. The components of HAART
must be taken at different times. - Non-compliance with protease inhibitor therapy is
of serious concern as the new virus that emerges
is resistant to the inhibitor being taken and
also resistant to other protease inhibitors.
44Anti-Hepatitis B Virus Agents
Figure 2. Timeline of evolution of HBV therapies,
United States.
45Interferons
- Interferon Alfa
- Endogenous proteins induce host cell enzymes
that inhibit viral RNA translation and cause
degradation of viral mRNA and tRNA . - Bind to membrane receptors on cell surface , May
also inhibit viral penetration, uncoating, mRNA
synthesis, and translation, and virion assembly
and release. - Pegylated interferon Alfa
- A linear or branced polyethylene gylcol (PEG)
moiety is attached covalently to interferon - Increased half-life and steady drug
concentrations
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47Interferons
- a limited treatment course (ie, only 1 year of
therapy), - lack of resistance development.
- Disadvantages include a high rate of
treatment-related adverse events. flu-like
symptoms increased body temperature, feeling
ill, fatigue, headache, muscle pain.
48Anti-Hepatitis C Virus Agents
- Approved
- Interferon-alpha (pegylated)
- Ribavirin
- In development
- Protease inhibitors
- Polymerase inhibitors
49- In pregnancy , a regimen of oral zidovudine
beginning between 14 and 34 weeks of gestation,
intravenous zidovudine during labor, and
zidovudine syrup to the neonate from birth
through 6 weeks of age has been shown to reduce
the rate of vertical (mother-to-newborn)
transmission of HIV by up to 23.